HIF1α as a central regulator in pulmonary fibrosis: a potential therapeutic target?

Pulmonary fibrosis represents a group of chronic disorders characterized by chronic fibrotic remodeling with limited therapeutic options. Despite heterogeneous etiologies, these disorders share convergent pathogenic mechanisms driven by persistent hypoxia within the fibrotic lung microenvironment. Hypoxia-inducible factor 1α (HIF1α) emerges as a central molecular integrator linking hypoxic stress to fibroblast activation, metabolic reprogramming, vascular dysfunction and chronic inflammation. In this review, we synthesize current mechanistic and disease-specific evidence supporting a pivotal role for HIF1α in pulmonary fibrosis. We describe how HIF1α orchestrates maladaptive repair responses across epithelial, endothelial, mesenchymal and immune cells, thereby sustaining self-amplifying profibrotic circuits. We further highlight how HIF1α activation, while context-dependent, represents a recurrent feature across distinct fibrotic lung diseases. Finally, we discuss current and emerging therapeutic strategies targeting HIF1α or its downstream pathways, emphasizing both their antifibrotic potential and challenges inherent to modulating hypoxia-responsive signaling in fibrotic lung diseases. Together, this review positions HIF1α as a unifying yet nuanced therapeutic target in pulmonary fibrosis. Created in BioRender. Reytier, C. (2026) https://BioRender.com/gld11jt .